Microparticle-based delivery of nucleic acids has gained particular attention in recent years in view of improving the potency of DNA vaccination. Such improvement has been reported by encapsulation of pDNA within biodegradable microparticles or through surface adsorption on cationic microparticles. However, the intrinsic intracellular barriers for gene delivery to antigen presenting cells (APCs) have not been adequately addressed in the rational design of delivery systems for DNA vaccines. Here we report synthesis and characterization of biodegradable microparticles that (a) can passively target phagocytic APCs, (b) have intrinsic buffering ability that might allow for enhanced phagosomal escape, (c) are not cytotoxic and (d) have improved APC transfection efficiency. Branched polyethyleneimine (b-PEI) was covalently conjugated using carbodiimide chemistry to the surface of poly(lactide-coglycolide) (PLGA) microparticles to create cationic microparticles capable of simultaneously delivering both DNA vaccines as well as other immunomodulatory agents (cytokines or nucleic acids) within a single injectable delivery vehicle. Our results indicate that covalent conjugation of b-PEI allows efficient surface loading of nucleic acids, introduces intrinsic buffering properties to PLGA particles and enhances transfection of phagocytic cells without affecting the cytocompatibility of PLGA carriers.